The immune system has the ability to remember an encounter with an antigen for decades or even a lifetime. Exploration of this property and the induction of a long-term, pathogen-specific immune response led to the phenomenal success of vaccination programs against infectious diseases that still represent some of the most impressive triumphs of modern medicine and immunology. The immune system also plays a crucial role in the control of tumor development, as now convincingly documented by studies carried out on immunodeficient mice. Thus there is a hope that similar to the success of vaccination against infections, immune responses could also be harnessed to protect against cancer. This enthusiasm has been further fueled by recent advances in our understanding of the mechanisms controling activation of the immune system, together with the progress in laboratory techniques that allows manipulation of components of the immune system in vitro and the generation of increasingly sophisticated vaccines. Some of the important findings relevant to the development of tumor immunotherapeutic strategies include:
| • | Advances in the identification of tumor antigens Citation[1,2]; | ||||
| • | Identification of mechanisms used by the innate immune system to sense the presence of pathogens or other ‘danger’ signals via pattern-recognition receptors, such as Toll-like receptors expressed on antigen-presenting cells Citation[3]; | ||||
| • | Identification of dendritic cells and their activation through pattern-recognition receptors as the key event in the initiation of an antigen-specific primary immune response Citation[4]; | ||||
| • | Characterization of regulatory T cells and their mechanism of action Citation[5]. | ||||
However, clinical trials attempting to induce an effective immune response in patients with cancers have only had a limited success. Although administration of antitumor vaccines usually induced a detectable antitumor-specific immune response, the impact on tumor progression was limited Citation[6]. As all above-mentioned areas of research have recently been extensively reviewed, I would like to identify some caveats and misunderstandings of current efforts to induce tumor immunity and discuss a few novel concepts in harnessing the immune system in the fight against cancers.
There are a large number of animal models where the administration of a tumor vaccine prevents tumor growth upon subsequent challenge with a live tumor. Opponents of antitumor immunization often claim that the results of animal studies have failed to translate in human settings, as clinical trials with antitumor vaccines have been unsuccessful. However, this is a big misconception. There is a fundamental difference between successful vaccines against cancer in animal models and clinical trials conducted in humans. Vaccines in animal models have largely been tried and proven effective in the preventive setting (preventive vaccination). By contrast, vaccination against cancer has generally been attempted in the context of therapy (therapeutic vaccination) in patients who already have advanced tumors and have received immunosuppressive chemotherapy. In fact, the lack of therapeutic benefit in clinical trials is not so surprising as therapeutic vaccination in mice also failed to suppress tumor growth in most cases. Therapeutic vaccination in mice is only effective if it is initiated very early after tumor challenge, a prerequisite that has not been fulfilled in any clinical trial.
Genetically engineered mice (GEM) harboring activating mutations in important oncogenes or inactivated tumor-suppressor genes have now become available for experimental studies Citation[7]. These mice have a strong predisposition to the development of a particular tumor, depending on the germ-line mutation. Importantly, tumorigenesis in some of these mice resembles, to certain degree, the natural course of disease in humans, as it seems to progress through the stages of dysplasia and preneoplasia to the clinically manifested malignant tumors. This allows monitoring of the immune response throughout the entire natural history of the disease. Although relatively few studies have been completed, it is evident that preventive tumor vaccination can substantially delay or completely block tumor onset driven by potent oncogenes if initiated early, in other words, before or soon after the development of preneoplastic lesions Citation[8]. Studies in GEM have also provided useful information regarding effector mechanisms best suited for tumor prevention. As opposed to the prevailing view that the induction of cytotoxic T cells is crucial for the clearance of tumor cells, studies in preventive settings point to a need to induce coordinated humoral and cellular immune responses consisting of both innate and adaptive immune mechanisms. Altogether, if interpreted appropriately, preclinical studies in mice do not contradict the results achieved in clinical trials in advanced cancers. However, they indicate that the focus of clinical vaccination trials should shift towards patients with less advanced disease.
Ironically, none of the premises derived from animal studies have been fulfilled in recent clinical trials that enrolled patients with advanced, often metastatic, disease, heavily pretreated with chemotherapy in which other therapeutic approaches had failed. It would be unfair and illusory to expect radical clinical responses and to interpret the failure of antitumor vaccination in these settings as general proof of its inefficiency. In fact, the target population that is likely to profit the most from anti-tumor vaccination is the population of tumor-free individuals at increased risk of cancer. The administration of tumor vaccines prior to the development of cancer would represent a true preventive vaccination.
Without considering the technical and methodological aspects of cancer vaccine production, such as type of tumor antigen, choice of adjuvant, dose, frequency and duration of vaccine administration, I would like to speculate briefly on potential candidates for preventive cancer vaccination. By analogy to epidemiological terminology, immune prevention of cancer in clinical settings could be envisaged in several different scenarios.
Primary prevention requires the identification of individuals at risk of cancer development. This is already possible for patients with hereditary cancer syndromes (e.g., families with hereditary colorectal cancer or women with BRCA mutations) where specific mutations can be detected and the increased risk for cancer is well established. Individuals at risk for virally induced cancers are also candidates for primary immunoprevention of cancer. In this case, effective preventive vaccination against the causative infectious agent prevents the development of neoplasia. Results from population-based vaccination against the hepatitis B virus, known to be associated with liver cancer, have already shown a reduced cancer rate Citation[9]. The fact that cervical cancer is caused by human papillomavirus (HPV) infection also provides an exceptional opportunity to use vaccination as a tool for cancer prevention. A recent trial with a HPV subunit vaccine has demonstrated a 100% prevention of persistent HPV16 infection and HPV16-induced cervical dysplasias Citation[10]. Although the effect on cervical cancer incidence will only be known after vaccinated individuals reach the age at which the cancer arises, these results are very promising.
Secondary prevention is feasible in patients with preneoplastic lesions, wherein preventive antitumor vaccination should prevent progression to malignant tumors. Examples of the latter are patients with colon polyps, oral leukoplakia and cervical intraepithelial neoplasia or monoclonal gammopathy of unknown significance. There is a growing body of evidence that preneoplastic cells can alert various physiological repair and control mechanisms, including the immune system Citation[11,12]. Characterization of preneoplasia-specific immune responses could not only identify important tumor antigens but detection of an active immune response against tumor cells in the early stages of transformation could also represent a very specific and sensitive tool for the diagnosis of preneoplastic states.
With regards to tertiary prevention, many tumors can be eradicated or substantially reduced by current treatment modalities. If the standard treatment does not result in the complete eradication of the tumor, tumor cells gradually repopulate depending on the number of progenitor cells left after the initial treatment and the tumor eventually returns. Cancer vaccines could be used as a form of adjuvant therapy designed to elicit and boost antitumor immunity in patients with minimal residual disease, thus preventing or delaying disease recurrence. Attention has to turn to patients with minimal residual disease. In a number of diseases, especially in hematological malignancies, the level of minimal residual disease can be assessed by detection of specific molecular markers (e.g., chromosomal translocations, monoclonal T-cell receptors or immunoglobulin gene rearrangements in leukemias) and has been shown to correlate with prognosis Citation[13,14]. Standardized detection of minimal residual disease has now been incorporated into therapeutic protocols and therapeutic decisions are made based on its level. Apart from patients with known predisposition for cancer or with preneoplastic disease, patients with rising levels of residual disease thus represent potential candidates for the validation of the concept of immunotherapy.
Despite the fundamental differences between human and mouse immunity, experimental data in both systems indicate that antitumor vaccination could prevent cancer progression if administered early in the course of the disease and that the chance to control tumor growth progressively declines with growing mass of tumor cells. These data argue for the change of current emphasis for harnessing antitumor immunity from therapy of advanced disease to prevention of cancers in genetically prone individuals and to immunotherapy of patients with preneoplastic or minimal residual disease Citation[15].
Acknowledgements
I would like to thank Madhav Dhodapkar for fruitful discussions and continuous support. R Spisek is partially supported by project MSM 0021620812 from The Czech Ministry of Education.
References
- Jager D, Taverna C, Zippelius A et al. Identification of tumor antigens as potential target antigens for immunotherapy by serological expression cloning. Cancer Immunol. Immunother.53, 144–147 (2004).
- Boon T, Cerottini JC, Van den Eynde B et al. Tumor antigens recognized by T lymphocytes. Annu. Rev. Immunol.12, 337–365 (1994).
- Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses. Nat. Immunol.5, 987–995 (2004).
- Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature392, 245–252 (1998).
- Shevach EM, DiPaolo RA, Andersson J et al. The lifestyle of naturally occurring CD4+ CD25+ Foxp3+ regulatory T cells. Immunol. Rev.212, 60–73 (2006).
- Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving beyond current vaccines. Nat. Med.10, 909–915 (2004).
- Green JE, Hudson T. The promise of genetically engineered mice for cancer prevention studies. Nat. Rev. Cancer5, 184–198 (2005).
- Lollini PL, Cavallo F, Nanni P et al. Vaccines for tumour prevention. Nat. Rev. Cancer6, 204–216 (2006).
- Viviani S, Jack A, Hall AJ et al. Hepatitis B vaccination in infancy in The Gambia: protection against carriage at 9 years of age. Vaccine17, 2946–2950 (1999).
- Koutsky LA, Ault KA, Wheeler CM et al. A controlled trial of a human papillomavirus type 16 vaccine. N. Engl. J. Med.347, 1645–1651 (2002).
- Dhodapkar MV, Krasovsky J, Osman K et al. Vigorous premalignancy-specific effector T cell response in the bone marrow of patients with monoclonal gammopathy. J. Exp. Med.198, 1753–1757 (2003).
- Bartkova J, Horejsi Z, Koed K et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature434, 864–870 (2005).
- Goulden N, Bader P, Van Der Velden V et al. Minimal residual disease prior to stem cell transplant for childhood acute lymphoblastic leukaemia. Br. J. Haematol.122, 24–29 (2003).
- Sramkova L, Muzikova K, Fronkova E et al. Detectable minimal residual disease before allogeneic hematopoietic stem cell transplantation predicts extremely poor prognosis in children with acute lymphoblastic leukemia. Pediatr. Blood Cancer (2006).
- Spisek R, Dhodapkar MV. Immunoprevention of cancer. Hematol. Oncol. Clin. North. Am.20, 735–750 (2006).